Andrés Grases, the publisher of the Transhuman Plus website (http://transhumanplus.com/) interviews U.S. Transhumanist Party Chairman Gennady Stolyarov II at RAAD Fest 2018 in San Diego, CA, on September 23, 2018. During the course of this conversation, both the contemporary state of transhumanist politics and future directions are covered – along with the challenges to reforming the educational system, the need to create open access to academic works, the manner in which the transition toward the next era of technologies will occur, the meaning of transhumanism and its applications in the proximate future – including promising advances that we can expect to see during the next several years.

Editor’s Note: In this article, Keith Comito and Elena Milova positively discuss new a FDA regulatory framework on RMAT (regenerative medicine advanced therapies) and on how it benefits the healthy-life-extension community. This article was originally published by the Life Extension Advocacy Foundation (LEAF).

The first draft guidance addresses how the FDA intends to optimize its regulatory requirements for devices used in the recovery, isolation, and delivery of RMATs (regenerative medicine advanced therapies), including combination products.

The second document explains what expedited programs may be available to sponsors of regenerative medicine therapies and describes what therapies may be eligible for RMAT designation.

According to new FDA regulations, a drug is eligible for designation as an RMAT if:

The drug is a regenerative medicine therapy, which is defined as a cell therapy, therapeutic tissue engineering product, human cell and tissue product, or any combination product using such therapies or products, except for those regulated solely under Section 361 of the Public Health Service Act and part 1271 of Title 21, Code of Federal Regulations;

The drug is intended to treat, modify, reverse, or cure a serious or life-threatening disease or condition; and

Preliminary clinical evidence indicates that the drug has the potential to address unmet medical needs for such disease or condition

We hope that this joint project will support the improvement of US regulations that concern these innovative treatments and will make the overall regulatory landscape more friendly. Below, we cite the most important notes from our resulting paper.

Last week, the Niskanen Center joined with the Life Extension Advocacy Foundation in filing comments to the Food and Drug Administration (FDA), offering our support for the agency’s new regenerative medicine advanced therapy (RMAT) designation draft guidance for industry.

Although there are opportunities for marginal improvements to the guidance, and FDA approval processes more generally, we are happy to see that the agency chose to include gene therapies in its interpretation of what qualifies as a regenerative medicine therapy.

Under section 3033 of the 21st Century Cures Act, the FDA was tasked with developing an accelerated approval process for regenerative advanced therapies. Such therapies would qualify for expedited review and approval so long as the drug (a) met the definition of a regenerative medicine therapy, (b) was “intended to treat, modify, reverse, or cure a serious condition,” and (c) “has the potential to address unmet medical needs” for a serious disease or condition. Unfortunately, the bill’s definition of a regenerative medicine advanced therapy was unclear on whether gene therapies, in particular, would qualify. Luckily, the FDA clarified this point. As the RMAT guidance document notes:

gene therapies, including genetically modified cells, that lead to a durable modification of cells or tissues may meet the definition of a regenerative medicine therapy. Additionally, a combination product (biologic-device, biologic-drug, or biologic-device-drug) can be eligible for RMAT designation when the biological product component provides the greatest contribution to the overall intended therapeutic effects of the combination product.

This is an excellent development and one that portends immense benefits for future gene therapy applications submitted for FDA approval. According to the guidance, the new RMAT designation, unlike other fast-track approval and review processes, “does not require evidence to indicate that the drug may offer a substantial improvement over available therapies.” Liberalizing the threshold standards of evidence for RMAT designation ensures that future gene therapies will encounter fewer unnecessary roadblocks in delivering more effective and innovative treatments for individuals suffering from debilitating diseases.

As we note in our concluding remarks:

Overall, we consider the RMAT guidance to be a stellar improvement over other expedited programs, especially in its qualifying criteria. However, greater clarity is needed in order to capture the benefits of more advanced cell therapies that can help contribute to the healthy aging and well-being of American citizens. As FDA Commissioner Scott Gottlieb recently noted: “The benefits of [gene therapy] science—and the products that become available—are likely to accelerate. How we define the modern framework for safely advancing these opportunities will determine whether we’re able to fully realize the benefits that these new technologies can offer.”

We agree wholeheartedly. Developing a regulatory framework that accommodates safety and innovation will be a key determinant of how quickly the benefits of regenerative medicine, gene therapy, and anti-aging research revolutionize the lives of Americans. This guidance is an important and promising step in the right direction. With the right modifications, it can help usher in a new age of healthcare improvement for individuals from all walks of life.

About Elena Milova

As a devoted advocate of rejuvenation technologies since 2013, Elena is providing the community with a systemic vision how aging is affecting our society. Her research interests include global and local policies on aging, demographic changes, public perception of the application of rejuvenation technologies to prevent age-related diseases and extend life, and related public concerns. Elena is a co-author of the book “Aging prevention for all” (in Russian, 2015) and the organizer of multiple educational events helping the general public adopt the idea of eventually bringing aging under medical control.

About Keith Comito

Keith Comito is President of LEAF / Lifespan.io and a long-time advocate of longevity research. He is also a computer programmer, mathematician, musician, lover of life and perhaps a man with too many hobbies. He earned a B.S. in Mathematics, B.S. in Computer science, and M.S. in Applied Mathematics at Hofstra University, where his work included analysis of the LMNA protein.

About LIFE EXTENSION ADVOCACY FOUNDATION (LEAF)

In 2014, the Life Extension Advocacy Foundation was established as a 501(c)(3) non-profit organization dedicated to promoting increased healthy human lifespan through fiscally sponsoring longevity research projects and raising awareness regarding the societal benefits of life extension. In 2015 they launched Lifespan.io, the first nonprofit crowdfunding platform focused on the biomedical research of aging.

They believe that this will enable the general public to influence the pace of research directly. To date they have successfully supported four research projects aimed at investigating different processes of aging and developing therapies to treat age-related diseases.

The LEAF team organizes educational events, takes part in different public and scientific conferences, and actively engages with the public on social media in order to help disseminate this crucial information. They initiate public dialogue aimed at regulatory improvement in the fields related to rejuvenation biotechnology.

What is ageing? We can define ageing as a process of accumulation of the damage which is just a side-effect of normal metabolism. While researchers still poorly understand how metabolic processes cause damage accumulation, and how accumulated damage causes pathology, the damage itself — the structural difference between old tissue and young tissue — is categorized and understood pretty well. By repairing damage and restoring the previous undamaged — young — state of an organism, we can really rejuvenate it! It sounds very promising, and so it is. And for some types of damage (for example, for senescent cells) it is already proved to work!

Today in our virtual studio, somewhere between cold, rainy Saint-Petersburg and warm, sunny Mountain View, we meet a famous person. I hope everyone knows Aubrey de Grey — the man who fell to Earth in order to change our vision of ageing, to fight with and to finally save us from it! For those of you who are not familiar with him, here is a brief introduction.

Dr. de Grey is the biomedical gerontologist who researched the idea for and founded SENS Research Foundation. He received his BA in Computer Science and Ph.D. in Biology from the University of Cambridge in 1985 and 2000, respectively. Dr. de Grey is Editor-in-Chief of Rejuvenation Research, is a Fellow of both the Gerontological Society of America and the American Aging Association, and sits on the editorial and scientific advisory boards of numerous journals and organizations. In 2011, de Grey inherited roughly $16.5 million on the death of his mother. Of this he assigned $13 million to fund SENS research.

I will not ask Dr. Aubrey de Grey any of those stupid questions that journalists usually annoy him with, about his appearance, overpopulation and so on. Instead, we will talk about science and engineering that will rejuvenate our bodies and allow us to be healthy and live longer (I mean really much longer). Because of the recent breakthroughs in many fields, from bionics and applied physics to molecular biology and regenerative medicine, it can (and, I am sure, will) be sooner than you think.

Interview

Feinerman: Hello, Dr. de Grey!

de Grey: Hi — thanks for interviewing me.

Feinerman: In 2012, I read an article by David Sinclair, where he described reversing the loss of mitochondrial function in old mice cells by using NAD+. I felt this was a major change. The past five years have been remarkable! Now every day I read new articles and news about age reversal. In three years, there has been the creation of a few dozen new bioengineering companies whose main goal is to reverse ageing. Billions of dollars are now invested in this area. I believe we will remember 2016–2017 as the most important years. Do you share this feeling?

Note: The first Phase 1 human ageing reversal trials (GDF, Myostatin) will be in a year or two, and George Church discusses how to affordably rejuvenate the whole body! The first version of human CRISPR/Cas9 was created in 2013, and now it is ready for use. In 2015 eGenesis began to work on pigs for xenotransplantation and now they claim they have created retrovirus-free pigs! In 2016 Juan Carlos Izpisua Belmonte has reprogrammed cells by using special factors and reverted back the biological clock in live mice. And this is only a tiny fraction of news!

de Grey: Yes and no. Yes, in the sense that there are indeed more and more exciting breakthroughs being made in the lab — and of course I am very proud that SENS Research Foundation is responsible for some of them. But no, in the sense that there is still a terribly long way to go; we need to fix a lot of different things in order to get rid of ageing, and for some of them we are still at a very early stage in the research.

Feinerman: George Church said that his lab is already reversing ageing in mice and that human applications may only be a few years away. He said: “We have 65 gene therapies that are being tested in mice and larger animals. If they go well, we will go straight into human trials.” Church predicts that age reversal will become a reality within 10 years as a result of the new developments in genetic engineering. However, he warns that age reversal at a molecular level doesn’t necessarily mean that everything else rejuvenates. No one knows what age reversal will mean for humans. Anyway, all that sounds very promising?

de Grey: George is exactly right, both in his urgency and optimism, and also in his caution about how much we don’t yet know.

Feinerman: You have really changed the world’s opinion, but now you are behind the scenes. I regularly read about new breakthroughs in the news while I don’t see much about your work, even though research in SENS is more fundamental in general! When I went to the SENS web page, I was wondered how much you do. This seems like an injustice and can it be fixed?

de Grey: Oh, I’m still quite prominent — I’m still doing just as many talks and interviews as ever. If, to some extent, my contributions are now being overshadowed by other people’s breakthroughs, that’s a good thing! I have always said that my goal is to advance the crusade far enough that I can retreat into glorious obscurity because others are doing my job better than me.

Feinerman: For many people, their appearance is as important as their health. When you say that SENS 1.0 panel of therapies can rejuvenate people from 60 to 30, do they look like 30? Or can they look like 30?

de Grey: Definitely yes. When we thoroughly rejuvenate the inside of the body, the outside is the easy part!

Feinerman: Can we now say that biomedical engineering and biotechnology have entered an exponential phase?

de Grey: I think we can just about say that, yes. It’s very exciting.

Ending Aging Revisited

Feinerman: Your famous book Ending Aging was published 10 years ago. Would you like to make a new version?

de Grey: I probably should, at some point, but it’s not a priority, because the overall approach that we described in that book has stood the test of time: we have made plenty of progress, and we have not come across any unforeseen obstacles that made us change course with regard to any of the types of damage.

Note: If you have not read Ending Aging yet, I suggest you to do it as soon as possible, and to be more comfortable with the ideas we are discussing below, I highly recommend you to read the short introduction to SENS research on the SENS Research Foundation web page. Also, if you are interested in recent news and up-to-date reviews about [anti]ageing and rejuvenation research, the best place to look for is the Fight Aging! blog. Finally, if you are an investor or just curious, I highly encourage you to take a look at Jim Mellon’s bookJuvenescence.

Feinerman: You look for bacteria who feed on dead animals to find enzymes capable of breaking glucosepane. Do you consider insects? They can eat nearly everything — and much faster!

de Grey: Nice idea, but we’re looking for a different sort of eating. Insects eat stuff and excrete what they can’t digest, just like us. Bacteria are much more versatile.

Feinerman: Many insects have no special enzymes; instead, they rely on bacteria who do all the work. In any case they are a nice place to look for the enzymes!

de Grey: Yeah, well, not really. Insects have commensal bacteria, yes, but so do we. In general, though, bacteria that are living freely in the environment are more diverse than those in the guts of animals.

Feinerman: How do you find useful bacteria?

de Grey: We are using a “metagenomic” strategy for identifying enzymes that can break glucosepane: we take standard E. coli bacteria, we break one or two of their genes so that they become unable to synthesise one or another chemical (in this case typically arginine or lysine) so that they need to take it up from their surroundings, and then we add random DNA from the environment (which could come from any bacteria, even unculturable ones) and add bits of it to the E. coli. Very occasionally the new DNA may encode an enzyme that breaks glucosepane, and if so, the bacteria will grow even without any arginine or lysine in the environment, if (but only if) we give them glucosepane instead and they break it to create arginine and lysine.

Feinerman: In your book you proposed Whole-body Interdiction of Lengthening of Telomeres (WILT) — the removal of telomerase in all cells in order to prevent cancer and reseed the stem-cell population regularly. Is there any success in that? And wouldn’t it be simpler to use non-integrating telomerase therapy to safely lengthen telomeres, like the approaches developed by Sierra Sciences and BioViva?

de Grey: We are making progress there, yes; in particular we have shown that telomerase-negative stem-cell reseeding works for the blood. However, no, the problem with non-integrating telomerase is that it will extend cancer telomeres just as much as normal cells’ telomeres. I support that research, though, not least because there may be breakthroughs in combating cancer in other ways (especially with the immune system), in which case it would be much safer to stimulate telomerase systemically.

Feinerman: Now we have very precise CRISPR, and removing genes is easier than inserting ones, because you can target the same cell more than once. When we solve the delivery problem, would we be able to apply WILT?

de Grey: It’s being tried, but it is very difficult to make the removal selective.

Feinerman: There is growing evidence that epigenetic changes are highly organized and may be one of the causes of ageing. This allows some researchers to claim that ageing is a programme. It does not matter, however, how researchers see such changes — as a programme or as damage. By restoring the previous epigenetic profile by means of special reprogramming factors, we can turn an old cell into a young cell, and by resetting the profile, we can turn an adult cell into a pluripotent stem cell. Experiments show that restoring the epigenetic profiles of many cells in vivo rejuvenates an entire organism. What do you think? Maybe should we consider epigenetic changes as another type of damage in the SENS model, calling it EpiSENS?

de Grey: We need to be much more precise with definitions in order to answer your question. Epigenetic changes can be classified into two main classes: shift and noise. Shift means changes that occur in a coordinated manner among all cells of a given type and tissue, whereas noise means changes that occur in some such cells but not others, increasing the variability of that type of cell. Shifts are caused by some sort of program (genetic changes to the cell’s environment), so yes, they can potentially be reversed by restoring the environment and putting the program into reverse. Noise, on the other hand, is not reversible. And we have for several years worked on determining whether it happens enough to matter in a currently normal lifetime. We have not got to a definitive answer, but it’s looking as though no, epigenetic noise accumulates too slowly to matter, other than maybe for cancer (which, of course, we are addressing in other ways).

Feinerman: Should we use reprogramming factors to reverse the epigenetic programme?

de Grey: Probably not. There may be some benefits in doing so, as a way to restore the numbers of certain types of stem cells, but we can always do that by other methods (especially by direct stem cell transplantation), so I don’t think we will ever actually NEED to dedifferentiate cells in vivo.

Feinerman: One thing keeps me out of bed at night: the fear that stochastic nuclear DNA damage and mutations may play a big role in ageing. Ten years ago you proposed that most of the cells which have critical DNA mutations either undergo apoptosis, become senescent, or become cancerous. But if mutations are not critical, cells will live, accumulate them — one broken protein here, another one there — and it will finally lead to malfunction of the organ.

de Grey: Don’t worry. These mutations don’t accumulate nearly fast enough to harm us, because they are prevented by the same machinery that prevents cancer for a currently normal lifetime, and cancer can kill us as a result of only one cell doing the wrong thing, whereas non-critical mutations would need to affect a huge number of cells in order to affect the function of a tissue.

Feinerman: If it is proved that nuclear DNA damage and mutations play a role in ageing, do you have something in your pocket? I believe you already thought on that. How will we fix the problem? Maybe, extensive stem-cell therapy (like the proposed Whole-body Induced Cell Turnover)?

de Grey: Right. But they don’t play a role.

Note: Whole-body Induced Cell Turnover (WICT) consists of the qualitative and quantitative coordination of targeted cell ablation with exogenous cell administration so as to effect the replacement of a patient’s entire set of endogenous cells with exogenous cells (of the same quantity and cell type as the ablated endogenous cells they are replacing) derived from human pluripotent stem cells and directionally differentiated in vitro prior to their administration. The idea of WICT was firstly proposed in 2016 and improved in 2017.

The aim of WICT is the removal from the organismal environment of accumulated cellular and intracellular damage present in the patient’s endogenous cells, including telomere depletion, nuclear DNA damage and mutations, mitochondrial DNA damage and mutations, replicative senescence, functionally deleterious age-related changes in gene expression, and accumulated cellular and intracellular aggregates.

Feinerman: What do you think on the WICT? Combined with WILT, it looks like an all-in-one solution when implemented.

de Grey: The general idea of accelerating cell turnover is definitely a good one. It is a bit like the idea of replacing whole organs: if you replace the entire structure, you don’t need to repair the damage that the structure contains. However, also like replacement of organs, it has potential downsides, because evolution has give us a particular rate of turnover of particular cells, and the function of each of our cell types is optimised for that. So it may end up being complicated, with many pros and cons.

Feinerman: While other rejuvenating therapies (excepting, maybe, OncoSENS) are achievable in the near future and don’t involve special genetic surgery, full allotopic expression has a really long way to go. What do you think of the mimic approaches, for example, NMN, which raises the NAD+ level and restores mitochondrial function in a cell?

de Grey: It may help to preserve health a little, but I think it is very unlikely to extend life by more than a year or two on average (and it could be even less than that). But we are working hard to develop better methods of gene therapy that may make allotopic expression practical sooner than people think.

Feinerman: Oh, can you unveil the mystery?

de Grey: Well, basically we are combining two technologies that are both very very safe (in the sense that they have very low incidence of random DNA damage) but they have complementary limitations. One is CRISPR, which can make small changes very safely to a chosen location in the genome but cannot insert more than very small amounts of new DNA. The other is a very neglected system called BXB1, which can insert large amounts but only into a location that does not exist in the mammalian genome. Our idea is to use CRISPR to insert the BXB1 “landing pad” at a good location and then to use BXB1 to insert our chosen engineered genes at that location. We are developing this at the Buck Institute in Brian Kennedy’s lab.

Feinerman: Thank you for your explanation! However, there is a big problem with all genetic therapies. We need to target every cell in the body, and now it is nearly impossible. Our best delivery systems involving adeno-associated viruses (AAV) available today have only 10–50% efficiency. We should honestly admit that we still have no universal instrument for introducing new genes in an adult human. How will you solve this problem?

de Grey: We believe that the approach I described in my earlier answer will achieve a much higher efficiency, and because its lack of off-target effects, it means it can be used at much higher titer.

Feinerman: The main SENS approach is to rejuvenate our own bodies, but also there is a regenerative medicine which involves tissue and organ engineering. Won’t it be easier to print or grow new organs instead of rejuvenating the old ones? Of course, we cannot replace everything, but we can replace some critical parts: we can grow a new heart, liver, muscles, and, indeed, skin.

Note: Tissue and organ engineering is among the most fast-growing areas of regenerative medicine. Engineers have already bio-printed or grown in bioreactors almost all human organs. Now they are used mostly for testing new therapies or drugs. The main problem why they cannot be used for transplantation now is the vascularisation challenge. While engineers can bio-print or grow arteries and big vessels, they are still unable to create the vasculature — the web of tiny vessels and capillaries within the organ. Companies like Organovo pursue this goal and promise to solve it within next decade.

de Grey: That’s absolutely correct. I expect that in the early days of implementing SENS, some organs will be easier to replace than to repair. However, of course, replacing an organ requires invasive surgery, so we will want to develop repair eventually.

Feinerman: You emphasize that stem-cell research is already a well-advanced field, and SENS has not needed to get involved in this area. As far as I know, many stem-cell therapies are for very specific diseases and not for rejuvenation. Or will we get it as a side-effect?

de Grey: As you know, I don’t think that “diseases of old age” should be called diseases at all — they are parts of ageing, so their treatment is definitely part of rejuvenation. A great example right now is Parkinson’s disease — there are several stem-cell clinical trials in progress or in preparation for it.

Feinerman: Do you mean they are parts of ageing like a runny nose and cough are parts of flu? So treating them separately is as foolish as treating a cough without addressing the flu virus.

de Grey: It’s even worse than that. Treating runny nose and cough makes some sense, because the body will get on with attacking the flu virus anyway, and it makes sense to be less miserable during that time. But with ageing, we’re just talking about different parts of a phenomenon that the body does not know how to attack.

Feinerman: What in your opinion will be the order of arrival of rejuvenating therapies?

de Grey: Well, a lot of the stem-cell side of things is in clinical trials already, and removal of amyloid is there, too, in the case of Alzheimer’s. Next on the list will probably be senescent-cell ablation, which Unity are saying will be in the clinic next year, and removal of intracellular garbage for macular degeneration will also be, courtesy of our spinout Ichor. The other three are harder, but they are all chugging along!

Feinerman: There are about twenty various types of amyloids, we can see some success in removing transthyretin and beta-amyloid. What about others? Can we scale success in removing the above two on the others?

de Grey: I’m very confident that the removal of other amyloids can be achieved using more or less the same methods that have worked against those two. The next one on my list would be islet amyloid, which contributes to diabetes.

Feinerman: As far as I know intracellular junk in the eyes is not lipofuscin per se but A2E, oxidized form of vitamin A. Is there any progress in removing true lipofuscin — the more widespread form of intracellular junk?

de Grey: We have funded some preliminary work on that, but it’s still early. The difficulty is that lipofuscin is very heterogeneous, made up of many different components. Our strategy is to target it more like the way we target the extracellular matrix: rather than breaking it down, we want to identify some key crosslinks that are protecting it from being degraded by our existing lysosomal machinery.

Feinerman: Now everyone is obsessed with “ageing biomarkers” and the “biological clock”. Are they valid conceptions? Is it possible to have a single “clock” for the whole body? Maybe can we just use every type of damage as a biomarker and keep it below certain threshold?

de Grey: I agree with you — ultimately, we still need to fix the damage, so there is not much more that indirect proxy measures can tell us. These indirect measures are useful today, though, when we don’t have those repair therapies, because they help us to see what interventions may (slightly) slow down the accumulation of damage.

WHO, FDA, and New Medicine

Feinerman: FDA has a very long approval for new therapies or drugs. What do you think on medical tourism and biohacking as an alternative way?

de Grey: There have always been places with less restrictive regulatory systems for new drugs — medical tourism is nothing new. I think the key thing we should be doing more of is making better use of those who choose to go abroad to get treated: we should make it as easy as possible for them to report on what treatment they received and how well it worked, any side-effects, etc., for a long time after the treatment, so that such information can be analysed and used to guide future research. The people who provide experimental therapies don’t have any incentive to gather such data themselves, so it usually never gets gathered.

Feinerman: Do the SENS Research Foundation or any associated companies hold regular meetings with the FDA to inform them and clear the way for the new rejuvenation medicine? Some components of the SENS 1.0 panel are already in development or clinical trials, and others will arrive during next 20 years. These new coming medicines use completely different, repair-based rather than compensatory, approaches and need different clinical-trials protocol and a whole new health-care paradigm. The transition period has already begun, and we should use it wisely, otherwise the US may become an outsider in the medical world.

de Grey: I look forward to the day when we have such meetings, but that’s a little way off. That’s OK, though, because companies that are pursuing various components of SENS are indeed having such discussions. The FDA and its counterparts worldwide are being kept up to speed.

Feinerman: We already have many amazing results in the lab which can save human lives just now, but the lack of funding and the heavily regulated medical system don’t give them any chance to be in clinics in the coming years. With the current pace of progress, they will already be outdated before clinical trials. Do you think that translational research becomes the bottleneck?

Note: Even though 90% of US deaths and at least 80% of US medical costs are caused by ageing:

These numbers speak for themselves; they are all you need to answer the question of when all of the discussed amazing therapies will be available in the clinics.

de Grey: I think things are improving. The idea of real rejuvenation is becoming more and more accepted. At this point, therefore, I would say that the main bottleneck is still at the earliest stage: the funding for work that is not yet investable.

Feinerman: The current WHO’s agenda is kind of a shame! They know that the fire is coming, but they prepare gasoline to put it out with. Do you agree that the conception of “healthy ageing” is a nonsense? Ageing cannot be healthy because if you are healthy you, well, do not age. The WHO forces people to be more comfortable with ageing instead of fighting with it. They recommend to spend billions to build more nursing houses and buy more wheelchairs instead of investing these money into rejuvenation biotechnology! It’s ridiculous!

de Grey: Well, I think we need to do both things: we need to maintain older people’s quality of life as best we can with the limited tools we have today, and we also need to develop better tools. Terms like “healthy ageing” are indeed double-edged: on the one hand there is, indeed, obviously no such thing, but on the other hand the terminology helps to emphasise that the purpose of all our work is to extend healthspan, with the extension of lifespan being simply a side-effect.

Rejuvenation Research Won’t Fund Itself

Feinerman: When I ask people to donate to SENS Research Foundation, they often say that their a few bucks don’t matter. Of course, they are wrong! Every dollar, even every cent matters! For example, how many people may read this? We assume 10,000. Well, if every of you will donate $50, only $50, per month, it will be over $5,000,000 per year! This sum will double current SENS budget. So, united we can change the world. We cannot and should not wait when governments and big pharma will fund rejuvenation research. (In fact they won’t; they will wait and see the first results.) We can do it ourselves! What can you say to our readers to encourage them?

de Grey: You are saying it really well. One way to say it is to calculate how many dollars it would take to save a life by donating to SENS. I estimate that a budget of $50 millions per year would let us go three times faster than now and would bring forward the defeat of ageing by about a decade. About 400 million people die of ageing in a decade, so that means donating to SENS has a bang-for-the-buck of roughly one life per dollar. No other cause comes anywhere near that.

Feinerman: Another doubt that people usually express is how does SENS Research Foundation do anything meaningful with such a small budget? While NIH and many others have hundreds of millions per year and cannot defeat ageing, SENS has only $5 millions per year. I answer that SENS is a highly efficient organization, goal-directed and result-oriented rather than process-oriented. Everyone can go through the SENS webpage and read last year’s annual report.

de Grey: Thank you! — that is indeed correct. Almost all research that is funded by governments is almost useless, because its effects on health will be tiny. SENS is different because it is a coherent, comprehensive plan for bring ageing under complete medical control.

Note: Unfortunately, I agree with Dr Aubrey de Grey. If you take a close look at NIH or NIA funded work… well… You will find hundreds of publications about obesity, lifestyle, air pollution, and their impact on longevity. Don’t you know that obesity, smoking, and much drinking of alcohol are bad for you? How can this information help us create a new cure against cancer, Alzheimer’s disease, or atherosclerosis? Do we really need another paper on it?

Also you can find many publications about calorie restriction and various genetic manipulations on worms and other model organisms that mimic it. Calorie restriction is everywhere! In the meantime, we have known for twenty years that CR does not work for humans. In 2015, $500,000 was given to projects like “A Large Randomized Trial of Vitamin D, Omega-3 Fatty Acids and Cognitive Decline”. It’s not a joke, it’s a real research work! You can find more here. All that is useless because you cannot use it to produce working rejuvenation therapies. Only a small part of this work is useful in the sense of defeating ageing. Do you know what is the most interesting? It’s all your taxes, all your money! Now you know that.

At the same time really important research projects like work on glucosepane breaker therapy (which will end many ageing pathologies like arterial stiffness, chronic inflammation, hypertension, strokes, and will save many lives) in Spiegel Lab at Yale is permanently underfunded and would be closed last year without financial support from SENS Research Foundation and German entrepreneur Michael Greve. Finally, the cost of implementing the working rejuvenation treatments in old mice would by current estimates be only 1–2% of the Apollo Program. And the same amount of money and time was already spend on Sirtuins which have obviously produced nothing.

Feinerman: Can you say what Project|21 is, why it is so important and how people can help?

de Grey: Project|21 is our name for our appeal to wealthy individuals. We of course welcome donations of any size, but at present it remains the case that most of our income is donated by a small number of wealthy donors, so it stands to reason that we are doing all we can to attract more of those. What other people can do to help is easy — donate what you can, and encourage donations by friends who are wealthier than you!

Note: Project|21 is a new initiative created by SENS Research Foundation to end age-related disease through human clinical trials, starting in 2021, through investment in rejuvenation biotechnology.

Through three new programs, the Bridge fund, The Center of Excellence, and The Alliance Program, Project|21 will deliver the perfect environment for this fusion of opportunity and investment.

$50 million in total funding is required for Project|21, at least half of which will come from the members of SENS Research Foundation’s Group|21. Group|21 will bring together 21 philanthropists, each donating between $500,000 and $5 million. Grants, grassroots efforts, and matching-fund strategies will provide the remaining support. $5 millions was already donated by German Internet entrepreneur Michael Greve. Thank you, Mr. Greve! You are our hero!

Feinerman: Some people prefer to donate not to the whole organisation, but rather to concrete project or lab. Of course, it is not among the most convenient and efficient ways to manage money, but anyway do you consider such an option?

de Grey: Certainly yes. We sometimes have projects that cannot be funded because there is too little “unrestricted” money to go around, but for the most part we are able to make it work, so absolutely, if anyone wants to restrict a donation to a particular project, we are totally happy to work with that.

Feinerman: Now cryptocurrencies and blockchain technologies allow completely new and efficient ways for crowdfunding and investment. We can see as various no-name companies easily raise tens of millions dollars via ICOs for clearly doubtful projects. This occurs while really important areas like generative medicine, rejuvenation biotechnology, or bionics are permanently experiencing an acute thirst of money. Do you consider an ICO for Project|21? I believe it perfectly fits into ICO conditions and requirements!

de Grey: It’s definitely important for us, and we are working closely with various people who are experts in cryptocurrencies. Vitalik Buterin, who created Ethereum, is actually a donor. We very much hope to bring in substantial funding via that route.

Human Psychology, Not the Science, is the Key Issue in Defeating Ageing

Feinerman: When I ask people whether they want to live hundreds of years, many of them say, “No”, but when I ask them, whether they want to look and feel like 30, while being 70, they say, “Yes, of course!” I hope, you got my idea: people are afraid of big numbers. People don’t want to live forever; they just want not to be sick forever, even though big numbers logically emerge from not being sick. Have you ever regretted your claims about big numbers and 1000-year lifespans? People usually understand them in the wrong way. Some your colleagues say that without such claims, your ideas would be much more popular.

de Grey: It has always been a difficult decision. Yes, people are afraid of big numbers, and they are really bad at reasoning about the distant future. But the most important thing, in the long term, is that I am saying what I believe to be true and that I can always give very thorough, logical answers to any challenges. If I had gone out in 2005 saying that we could live to 150 with rejuvenation tech, and people had said why not 250, I would not have had a good answer, and people would not have trusted me. In the end it always works best if you tell the truth.

Feinerman: What do you think of 2013 work “The hallmarks of ageing”, which is obviously inspired by your seven types of damage? They look more sophisticated, and harder to deal with. Anyway, does it mean that researches finally demystified ageing and recognised it as a solvable problem?

de Grey: You’re right, it was definitely a reinvention of SENS. It had quite a few mistakes, but the basic idea of divide-and-conquer damage repair is identical. It is not at all more sophisticated; it’s the same. And yes, it means that mainstream researchers have finally accepted that ageing is now pretty well understood and is solvable.

Feinerman: Although biomedical gerontologists are not afraid to speak about ageing any more, as was the case 10 or even 5 years ago, which itself is a very big step, they are still very skeptical — at least publicly — about our ability to put ageing under medical control in the foreseeable future. You know many of them in person. Is it their real opinion? Maybe, face to face, they are more optimistic?

Note: I think that gerontologists should take a lesson from physicists and engineers. When physicists realised that our Sun uses a nuclear fusion reaction, they were excited by the idea to build a fusion reactor. Being full of courage, they started to work and immediately came across many obstacles. Although the reaction itself is very simple, the processes behind it are complex.

However, engineers haven’t given up or said: “We don’t fully understand these processes, so let’s stop working and study the Sun for 100 years.” They continued to work as hard as they could, built many working prototypes, and now we are much closer to commercial nuclear fusion reactor than ever before. And they are full of optimism! If you ask any physicist, whether it is possible to build such a reactor, the answer would be, “Yes, of course!” And if you ask an engineer, “When can we build it?”, he would probably say: “20–25 years, and it can be much sooner, if we have enough funding.” Sounds similar, doesn’t it?

Ageing is the same. But when you ask a gerontologist whether we can defeat ageing, he would likely call you a crazy. Why? They are both engineering problems!

de Grey: Well, maybe some of them are slightly more optimistic in private than they are in public, but really no — the problem is that they are basic scientists, so they are trained not to believe anything for which they do not have direct evidence. They just don’t like to speculate about time frames, even in private.

Feinerman: Yeah. With the current pace of progress, anything beyond 2030 is an uncertainty. However, what I know exactly is that if we want to have something working in 2030, we should work very hard in the right direction right now. So why do many [anti]ageing researchers consciously or unconsciously choose the most inefficient and ineffective way — altering metabolism via genetic manipulations or medications to only slightly possibly modestly slow down ageing — and use that as a proof (!) that we cannot radically extend human health and lifespan? Such an example is ridiculous by itself and nearly impossible in any research or engineering area, except biomedical gerontology!

de Grey: That is not something specific to anti-ageing research. In all research areas, the leaders always think they are right and take a long time to understand radically new ideas.

Feinerman: Maybe that is the reason? Maybe we need to have fewer gerontologists who merely study ageing and more biomedical engineers who repair damage? In other words we should switch our focus from ageing research to rejuvenation engineering. Since ageing is an engineering problem, then from the gerontologists’ point of view it looks like “not my job” to reverse it.

de Grey: Exactly. The main problem is that until “only” 17 years ago, no one had any coherent plan for fixing ageing, so it made sense to carry on treating gerontology as a basic science in which the priority was to discover more about it rather than to manipulate it. And 17 years is not very long in science, so the people who are most senior and influential are still the people who formed their mindset in the pre-rejuvenation era.

Feinerman: Unfortunately, the vast majority of biomedical engineers, those who do actual rejuvenation research, do not want to be associated with any [anti]ageing business and life extension, are not involved in longevity discussions, and usually keep silence. When pressed, they, however, are not very optimistic about life extension. It’s quite surprisingly to hear such claims from cutting-edge researchers, especially from those who recently promised to print or grow all vascularised human organs by 2035 and grow new limbs by 2030. If it is not about life extension, then what is it all about? Why do they behave in such a manner? Because of the pro-ageing trance? Or because they are too specialised and cannot see the whole picture?

For example, cell engineers make predictions as though there will be no progress in bionics, and bionics engineers make predictions as though there will be no progress in cell engineering. Each technology alone will not likely be te game changer, but when combined their impact will be enormous!

de Grey: You’ve got it. These technologies are developed largely independently of each other, so their leaders are largely unaware of how much progress is being made in the other areas. Since SENS is a divide-and-conquer approach, one cannot be optimistic about the overall outcome unless one is informed about all the components. That’s the main reason why I ran the Cambridge conference series starting in 2003, which is being revived in Berlin in March 2018 — to bring the leaders of these fields together.

Feinerman: Thank you very much for your amazing interview! Our conversation was wonderful! I wish you all your wishes come true as soon as possible. When we succeed, I hope we will shake our hands one hundreds years from now, walking along the waterfront of Mars City, which Elon Musk has promised to start to building in 2020s. Ah, and when you meet with him, remind him, please, that we will not be able to colonise Mars until we defeat ageing — because microgravity and cosmic radiation have the same implications on the human organism as premature ageing!

de Grey: Thank you for your support!

Afterwords

We live in the exciting era, The Era of Very Rapid Progress in science and technology — an era when many things which were merely science fiction only five years ago are common now, and things that are no more than science fiction now will be common in next five years. At the same time we live in The Era of Great Uncertainty — an era when our small everyday life decisions may have a huge impact on next several decades. One step to the right — and we may defeat ageing in twenty years. One step to the left — and the whole research areas will stagnate for another twenty years (as occurred in the case of glucosepane research).

New rejuvenation medicine is still very young and fragile, like the first spring flower after a dry and cold winter. In these days it especially needs our support! Even in such relatively advanced fields like stem cell or cancer research, there are gray, underfunded, and under-researched areas we need to care of.

Of course, you wish to know the time frames — when will we defeat ageing? You wish to know, will you personally benefit? Nobody knows. I intentionally did not ask Dr. Aubrey de Grey about the time frames and predictions. There will be no more time frames. Enough. Because they give you an illusion that some good clever guy will do all the work needed, while you may just relax, wait when he finishes, and “live long enough to live forever”. But he won’t! It is too big, too ambitious a project for one person. Now you know — your future is only in your hands. Not “live long enough…” but “work long enough…”! I always say that scientific and technological progress is a function of efforts — not of the time. The only way to get rid of a painful uncertainty and get to the definitive answer is to support meaningful rejuvenation research right now!

How can you help? Well, if you are a researcher yourself, then spend your time and money on the meaningful repair-based approach, which will produce working rejuvenation therapies in the foreseeable future. If you are a businessman — donate money to the SENS Research Foundation and its allies — Project|21, Methuselah Foundation, Forever Healthy Foundation, Life Extension Advocacy Foundation, or directly support research groups. Invest in the associated rejuvenation companies or found your own. If you are a celebrity, then use your fame to give attention to the problem and such research. If you are an ordinary person, well, you can encourage your more influential friends and do almost the same — just scale your abilities!

Some of you may ask: is it real? I hope we gave you enough evidence. Yes, of course, it’s real. Mover, it’s already happening! The right question, however, is whether it is happening fast enough to help us — currently living adult persons. And the answer is, probably, no. Of course, there may (and likely will) be many unexpected breakthroughs, but we should not rely on probability and scientific serendipity when we talk about human lives (especially our own). We should rely on a well-written plan, a reasonable budget and our efforts.

So the next question is, “Can we speed up the progress?” Yes, we can! All we need to do is what Dr. Aubrey de Grey said many times before and what I have just said above — unite against our main enemy and help researchers. But will we? Although people rarely think and behave rationally, I prefer to be cautiously optimistic! See you on Mars!

“One of the major hurdles limiting traditional cell therapies is low levels of engraftment and retention, which is caused in part by cells only being able to engraft at locations of existing cell loss, and by the fact that many of those vacancies have already become occupied by ECM and fibroblasts (i.e. scar tissue) by the time the cells are administered, long after the actual occurrence of cell loss. The crux underlying ICT is to coordinate endogenous cell ablation (i.e. induced apoptosis) with replacement cell administration so as to manually vacate niches for new cells to engraft, coordinating these two events in space and time so as to minimize the ability for sites of cell loss to become occupied by ECM and fibroblasts. This would be done in a gradual and multi-phasic manner so as to avoid acute tissue failure resulting from the transient absence of too many cells at any one time. While the notion of endogenous cell clearance prior to replacement cell administration has become routine for bone marrow transplants, it isn’t really on the horizon of researchers and clinicians working with solid tissues, and this is something we’d like to change,” said Franco Cortese, Deputy Director and Trustee of the Biogerontology Research Foundation, and lead author on the paper.

Cell-type and tissue-specific rates of induced turnover could be achieved using cell-type specific pro-apoptotic small molecule cocktails, peptide mimetics, and/or tissue-tropic AAV-delivered suicide genes driven by cell-type specific promoters. Because these sites of ablation would still be “fresh” when replacement cells are administered, the presumption is that the patterns of ablation will make administered cells more likely to engraft where they should, in freshly vacated niches where the signals promoting cell migration and engraftment are still active. By varying the dose of cell-type targeted ablative agents, cell type and tissue-specific rates of induced turnover could be achieved, allowing for the rate and spatial distribution of turnover to be tuned to the size of the tissue in order to avoid ablating too many cells at once and inadvertently inducing acute tissue failure.

“Cell therapies are limited by low levels of engraftment, and in principle their ability to improve clinical outcomes is limited by the fact that they can only engraft at locations of existing cell loss. Conversely, therapeutic tissue and organ engineering requires surgery, is more likely to introduce biochemical and mechanical abnormalities to tissue ultrastructure through the decellularization process, and is fundamentally incapable of replacing distributed tissues and structures with a high degree of interconnectivity to other tissues in the body. The aim of ICT is to form a bridge between these two main pillars of regenerative medicine, extending the efficacy of cell therapies beyond a patch for existing cell loss and accomplishing the aim of tissue and organ engineering (i.e. the replacement and regeneration of whole tissues and organs) while potentially remaining free of some of their present limitations,” said Giovanni Santostasi, co-author on the paper and a researcher at the Feinberg School of Medicine, Northwestern University.

While future iterations of the therapy could use patient-derived cells, such as ESCs derived via somatic cell nuclear transfer (SCNT) or iPSCs derived from nuclear reprogramming, shorter-term applications would likely use existing stem cell lines immunologically matched to the patient via HLA matching. The authors contend that the cloning of adult organisms with normal lifespans from adult somatic cells testifies to the fact that adult cells can be rejuvenated and used to produce a sufficient quantity of daughter cells to replace the sum of cells constituting adult organisms, and that serial cloning experiments (in which this process is done iteratively, using an adult cell of each subsequent generation to derive the next) attests to this fact even more strongly.

“ICT could theoretically enable the controlled turnover and rejuvenation of aged tissues. The technique is particularly applicable to tissues that are not amenable to growth ex vivo and implantation (as with solid organs) – such as the vascular, lymphatic, and nervous systems. The method relies upon targeted ablation of old, damaged and/or senescent cells, coupled with a titrated replacement with patient-derived semi-differentiated stem and progenitor cells. By gradually replacing the old cells with new cells, entire tissues can be replaced in situ. The body naturally turns over tissues, but not all tissues and perhaps not optimally. I am reminded of the quote attributed to Heraclitus: ‘No man ever steps in the same river twice, for it’s not the same river and he’s not the same man,'” said Sebastian Aguiar, a coauthor on the paper and researcher at the Swammerdam Institute of Life Sciences, University of Amsterdam.

“Reversing aging in humans will require a multi-step approach at multiple levels of the organismal organization. In situ targeted ablation of the senescent cells and regeneration will be an important component of comprehensive anti-aging therapies,” said Alex Zhavoronkov, Chief Science Officer of the Biogerontology Research Foundation.

The researchers originally proposed ICT in 2016 in the context of biomedical gerontology as a possible means of preventing and/or negating age-related phenotypic deviation for the purposes of healthspan extension, and in this new paper they refine the methodological underpinnings of the approach, take a closer look at potential complications and strategies for their deterrence, and analyze ICT in the context of regenerative medicine as an intervention for a broader range of conditions based on disease or dysfunction at the cellular and intercellular level, with potential utilities absent from traditional cell therapies and tissue/organ engineering, the two main pillars of regenerative medicine. The intervention is still very much conceptual, and any potential utilities over other therapeutic modalities within regenerative medicine would need to be verified via preclinical studies, but their hope is to stimulate further research at this interface between geroscience and regenerative medicine.

The Biogerontology Research Foundation is a UK non-profit research foundation and public policy center seeking to fill a gap within the research community, whereby the current scientific understanding of the ageing process is not yet being sufficiently exploited to produce effective medical interventions. The BGRF funds and conducts research which, building on the body of knowledge about how ageing happens, aims to develop biotechnological interventions to remediate the molecular and cellular deficits which accumulate with age and which underlie the ill-health of old age. Addressing ageing damage at this most fundamental level will provide an important opportunity to produce the effective, lasting treatments for the diseases and disabilities of ageing, required to improve quality of life in the elderly. The BGRF seeks to use the entire scope of modern biotechnology to attack the changes that take place in the course of ageing, and to address not just the symptoms of age-related diseases but also the mechanisms of those diseases.